The human histamine H3 receptor couples to GIRK channels in Xenopus oocytes

The histamine H3 receptor mediates inhibitory responses in the nervous system. Here, we demonstrate the coupling of the human histamine H3 receptor to G protein-coupled inward rectifier potassium (GIRK) channels in Xenopus oocytes, using voltage-clamp. The histamine H3 receptor agonist (R)-α-methylhistamine increased GIRK currents with an EC50 of 2.5 nM. The response to (R)-α-methylhistamine was inhibited by the specific antagonist/inverse agonist clobenpropit. GIRK channels represent a novel effector pathway for the histamine H3 receptor, also suggesting the use of electrophysiology assays in histamine H3 receptor drug screening, allowing for the resolution of G protein activation kinetics.